Nebulisation of Liquids

ABSTRACT

A device is disclosed for the preparation of nebulised droplets, for inhalation. The device has: a surface acoustic wave (SAW) transmission surface; a SAW transducer adapted to generate and propagate SAWs along the SAW transmission surface; and an array of cavities opening at the SAW transmission surface for containing a liquid. In operation, SAWs propagating along the SAW transmission surface interact with the liquid in the cavities to produce nebulised droplets of the liquid. Operation of the device results in a nebulised plume of droplets of average diameter in the range 1-5 μm.

BACKGROUND TO THE INVENTION Field of the Invention

The present invention relates to devices and methods for nebulisingliquids and liquid suspensions. The invention has particular, but notnecessarily exclusive, applicability to the preparation of therapeuticagents suitable for delivery to subjects.

Related Art

According to the World Health Organization (WHO) there are 235 millionpeople suffering from asthma and 64 million people with chronicobstructive pulmonary disease (COPD), leading to 3 million deaths peryear worldwide. Many millions also suffer with pulmonary infectiousdisease, cystic fibrosis, pulmonary hypertension and allergic rhinitisas well as other under-diagnosed chronic respiratory diseases. Estimatesof the cost of treating patients with such lung diseases, includingthose caused by tuberculosis (TB), COPD, cystic fibrosis, pneumonia,asthma and smoking was Euro 380 billion per annum (according to theEuropean Lung White Book of the European Respiratory Societyhttp://www.erswhitebook.org/ [accessed 12 Aug. 2014]).

Generally, patients with such respiratory diseases can be treated by theinhalation of aerosols or by alternate non-lung target routes such asoral and intravenous. One of the major advantages of the inhalationpulmonary route is that it can be targeted directly to the lung, andindeed, effective delivery of medication has been shown to be cruciallydependent upon the droplet size distribution within the aerosol ofmedicine [Brun et al 2000]. In general, if the size is too small (<0.5μm), the droplet will be exhaled, whilst if the size is too large (>5.0μm), the droplet will be trapped in the upper respiratory tract orthroat. The accepted wisdom is that pulmonary drug delivery requiresdroplet size distribution of the aerosols with diameters between about 1and 5 μm. Generating droplets of the optimum size allows medicine toreach and stay in the lungs at the correct therapeutic dose.

In addition to drug delivery, there are many other therapeuticstrategies that would benefit from localised and effective lung deliverythrough inhalation of aerosols. For example, both gene- and RNA-focusedtherapies can be targeted directly into the lung, providing an appealingstrategy for therapy. However, the efficiency of the approach, coupledwith the breadth/limitation of cell type(s) that are required to betargeted for therapeutic efficacy are important considerations. Forexample, targeting the lung epithelium in cystic fibrosis patients isextremely difficult due to certain anatomical and pathologicalchallenges and, as a consequence, has limited the clinical data obtainedwith a range of gene therapy approaches at both the pre-clinical andclinical level. Alternatively, targeting vascular cells is alsoappealing for treating patients with pulmonary arterial hypertension,although, again, effective delivery to the blood vessels necessitatesthat the therapeutic system (or droplet) has to transit defined andsubstantial anatomical barriers.

Thus, in short, there is a significant potential for improving thedelivery of drugs and biologics (including genes and RNA) by preparingsubstantially monodisperse aerosol droplets that are able to enter theappropriate tissue within the lung. Such a technique would enable newtherapies, providing access to a substantial market allowing thereduction of healthcare costs and the improvement of clinical outcomes.

SUMMARY OF THE INVENTION

The present invention has been devised in order to address at least oneof the above problems. Preferably, the present invention reduces,ameliorates, avoids or overcomes at least one of the above problems.

The present invention is based on the inventors' findings that thecontrolled actuation of a liquid suspension placed in an array ofsuitable cavities and excited by surface acoustic waves at suitablefrequencies can provide nebulised droplets of the liquid suspension witha tight distribution of droplet size.

The present invention has arisen from the inventors' work on fluidmanipulation using surface acoustic waves, disclosed in WO 2011023949,WO 2011060369, WO 2012114076 and WO 2012156755, the entire content ofeach of which is hereby incorporated by reference.

Nebulisers are used to administer medication or other therapies in theform of a mist inhaled into the lungs. These devices are currently usedto deliver various drugs for the treatment of cystic fibrosis, asthma,COPD and other respiratory diseases [Bo et al (2001)]. Nebulizers useoxygen, compressed air or ultrasonic power to break up medical solutionsand suspensions into small aerosol droplets that can be directly inhaledfrom the mouthpiece of the device.

There are considered to be four main nebuliser systems available at thetime of writing [Dolovich and Dhand (2011)]—conventional (usingcompressed air); ultrasonic (using crystals to vibrate the medication toa mist); vibrating mesh technology (using a vibrating metal mesh tocreate a mist of droplets from medication) and adaptive aerosols (usingvibrating technology mesh combined with optimal breathing monitoring).

All four classes of current nebuliser systems have limitations in theamount of drug that they can deliver to the lung, which is typically70%-80% of the dose. For patients this results in sub-optimal treatmentregimes with consequent impact on health and wellbeing. A particulardisadvantage of the ultrasonic nebuliser is that it is unable tonebulise suspensions and liquid with high viscosity and surface tension[Reboud, Wilson et al (2012); Reboud, Bourquin et al (2012); Qi et al(2008)]. Additionally, the present inventors consider that the dropletsize distribution provided by current nebuliser systems is too broad.

In the preferred embodiments of the present invention, there is providedcontrol over the aerosol droplet size and size distribution.Accordingly, the present invention has the potential to provide patientswith better [>95%] delivery of active drug per dose, thereby improvingtreatment outcomes e.g. infection control in cystic fibrosis or managingasthmatic conditions.

In a first preferred aspect, the present invention provides a device forthe preparation of nebulised droplets, the device having:

-   -   a surface acoustic wave (SAW) transmission surface;    -   a SAW transducer adapted to generate and propagate SAWs along        the SAW transmission surface; and    -   an array of cavities opening at the SAW transmission surface for        containing a liquid,

wherein, in operation, SAWs propagating along the SAW transmissionsurface interact with the liquid in the cavities to produce nebuliseddroplets of the liquid.

In a second preferred aspect, the present invention provides a methodfor the preparation of nebulised droplets, including providing a devicehaving a surface acoustic wave (SAW) transmission surface, a SAWtransducer adapted to generate and propagate SAWs along the SAWtransmission surface, and an array of cavities opening at the SAWtransmission surface, the method including the steps:

-   -   containing a liquid in the cavities; and    -   causing SAWs to propagate along the SAW transmission surface to        interact with the liquid in the cavities to produce nebulised        droplets of the liquid.

In a third preferred aspect, the present invention provides a method forthe preparation of nebulised droplets and their delivery to a subjectfor therapeutic treatment, including providing a device having a surfaceacoustic wave (SAW) transmission surface, a SAW transducer adapted togenerate and propagate SAWs along the SAW transmission surface, and anarray of cavities opening at the SAW transmission surface, the methodincluding the steps:

-   -   containing a liquid in the cavities;    -   causing SAWs to propagate along the SAW transmission surface to        interact with the liquid in the cavities to produce nebulised        droplets of the liquid; and    -   delivery of the nebulised droplets to the subject for        therapeutic treatment by inhalation.

In a fourth preferred aspect, the present invention provides amedicament in liquid form for use in a method for the preparation ofnebulised droplets of the medicament and their delivery to a subject fortherapeutic treatment, including providing a device having a surfaceacoustic wave (SAW) transmission surface, a SAW transducer adapted togenerate and propagate SAWs along the SAW transmission surface, and anarray of cavities opening at the SAW transmission surface, the methodincluding the steps:

-   -   containing the medicament in the cavities;    -   causing SAWs to propagate along the SAW transmission surface to        interact with the medicament in the cavities to produce        nebulised droplets of the liquid; and    -   delivery of the nebulised droplets to the subject for        therapeutic treatment by inhalation.

Preferably, the medicament is for treatment of one or more conditionsselected from the group consisting of: asthma; chronic obstructivepulmonary disease (COPD); pulmonary infectious disease; cystic fibrosis;pulmonary hypertension; allergic rhinitis; other chronic respiratorydiseases; pneumonia; tuberculosis (TB); lung disease such as lungdisease caused by smoking; diabetes; acute or chronic pain; multiplesclerosis; osteoporosis; infectious disease.

Preferably, the medicament comprises one or more compounds selected fromthe group consisting of:

Hydrocortisone (C₂₁H₃₀O₅);

Testosterone (C₁₉H₂₈O₂);

Dexamethasone (C₂₂H₂₉FO₅);

Budesonide (C₂₅H₃₄O₆);

Betamethasone (C₂₂H₂₉FO₅);

Cromolyn (C₂₃H₁₆O₁₁);

Formoterol (C₁₉H₂₄N₂O₄);

Imipramine (C₁₉H₂₄N₅);

Losartan (C₂₂H₂₃ClN₆O);

Terbutaline (C₁₂H₁₉NO₃);

Salbutamol (C₁₃H₂₁NO₃);

Zopiclone (C₁₇H₁₇ClN₆O₃);

Zaleplon (C₁₇H₁₅N₅O);

Zolpidem (C₁₉H₂₁N₃O);

Leflunomide (C₁₂H₉F₃N₂O₂);

Oxymetazoline (C₁₆H₂₄N₂O);

Insulin;

Morphine;

Interferon Beta 1a;

Parathyroid hormone;

Nicotine;

One or more antibiotics;

and pharmaceutically acceptable derivatives and salts thereof,optionally including excipients and carriers such as nanoparticles.

A review of candidate pharmaceutical compositions for pulmonary deliveryis set out in Eixarch et al (2010), the entire content of which ishereby incorporated by reference.

The first, second, third and/or fourth aspect of the invention may becombined with each other in any combination. Furthermore the first,second, third and/or fourth aspect of the invention may have any one or,to the extent that they are compatible, any combination of the followingoptional features.

The liquid may be one or more of: a pure compound; a mixture of liquids;a solution of one or more solutes in a liquid solvent; a suspension ofparticles (solid, substantially solid or liquid) in a carrier liquid; acolloid; an emulsion; nanoparticles or a suspension of nanoparticles.

The SAW transmission surface may be a surface of the SAW transducer.However, more preferably, the SAW transmission surface is a surface of asuperstrate coupled to the SAW transducer.

The present invention is not necessarily limited to any particularorientation. The term “superstrate” is used because in typicalimplementations of embodiments of the invention, this item is placed ontop of the SAW transducer. However, other orientations are contemplated,e.g. in which a corresponding substrate is placed under the transducer,yet the same effect of the invention can seen, in which the sample isnebulized from cavities in the surface of the substrate. Furthermore,the present invention is not necessarily limited to a planarconfiguration. For example, the transducer may be formed inside thesuperstrate, e.g. in a tubular configuration. Alternatively, thetransducer may be formed around the superstrate, with the superstrate inthe form of a tube (or hollow needle) held inside a transducer tube.This may be preferred, in order that a continuous (or quasi continuous)supply of sample fluid may be provided to the superstrate tube, with thenebulized plume provided at a free end of the superstrate tube.

Preferably, the superstrate is formed of a material which is imperviousto the liquid. This helps to avoid any (potentially contaminating)contact between the transducer and the liquid.

Preferably, the transducer comprises a layer of piezoelectric material.For example, the layer of piezoelectric material may be a sheet (e.g. aself-supporting sheet) of piezoelectric material. The layer ofpiezoelectric material may be a single crystal, such as a single crystalwafer. A suitable material is LiNbO₃. A preferred orientation for thecut for this material is Y-cut rot. 128°. This has a higherelectromechanical coupling coefficient than other orientations. Otherferroelectric materials may be used, e.g. PZT, BaTiO₃, SbTiO₃ or ZnO.Still further, materials such as SiO₂ (quartz), AlN, LiTaO₃, Al₂O₃ GaAs,SiC or polyvinylidene fluoride (PVDF) may be used. As an alternative toa single crystal, the material can be provided in polycrystalline oreven amorphous form, e.g. in the form of a layer, plate or film.

The transducer preferably further comprises at least one arrangement ofelectrodes. For example, the electrodes may be interdigitated. Morepreferably, the transducer comprises two or more arrangements ofelectrodes. In some embodiments, it is preferred that the transducer istunable, such that the lateral position of the SAWs emission train ismovable. For example, the slanted interdigitated arrangement ofelectrodes suggested by Wu and Chang (2005) can be used for thetransducer.

The superstrate may be permanently coupled to the piezoelectric layer,in the sense that it is not removable from the piezoelectric layerwithout damage to the device.

Alternatively, coupling between the transducer and the superstrate maybe achieved using a coupling medium, preferably a fluid or gel couplingmedium. The coupling medium may be an aqueous coupling medium, e.g.water. Alternatively, the coupling medium may be an organic couplingmedium, such as an oil-based coupling medium or glycerol. The couplingmedium provides intimate contact between the superstrate and thetransducer and allows the efficient transfer of acoustic energy to thesuperstrate from the transducer.

The advantage of providing the superstrate as a separate entity from thetransducer is very significant. Typical SAW transducers are complex tomanufacture. For this reason, they are typically expensive.Contamination of the transducer may be difficult or impossible toremove, if the liquid is allowed to come into contact with thetransducer. Alternatively, removal may not be cost-effective, or maydamage the transducer. However, it is strongly preferred that thetransducer can be re-used. Accordingly, it is preferred that the liquiddoes not contact the transducer but instead contacts the superstratecoupled to the transducer. The superstrate itself may be disposable(e.g. disposed of after a single use). The superstrate may be formed byvarious methods, such as microfabrication, embossing, moulding,spraying, lithographic techniques (e.g. photolithography), etc.

The cavities preferably have substantially the same shape. The SAWtransmission surface, in use, preferably is held substantiallyhorizontal. In this way, the cavities preferably open in the upwarddirection. The cavities may be closed at an end distal from the SAWtransmission surface. Alternatively, the cavities may be open at an enddistal from the SAW transmission surface.

The cavities may be substantially columnar in shape. In this way, thecross sectional shape of the cavities may be substantially uniform withdepth (a direction perpendicular to the SAW transmission surface). Forexample, the cross sectional shape of the cavities in the depthdirection may be rectangular, square, rounded, oval, elliptical,circular, triangular. Most preferably the cross sectional shape of thecavities in the depth direction is circular. The cross sectional area ofthe cavities may be uniform with depth. However, in some embodimentsthis may not be the case, allowing the cavities to have a crosssectional area which narrows, expands or undulates with depth. Forexample, funnel-shaped cavities may be provided (such cavities beingcapable of being formed using a KOH etch for example), to providesuitable volume in the cavity to retain the liquid.

The cavities may have an internal structure. For example, there may beprovided one or more pillars upstanding in the cavities, wallsprojecting into the cavities or other projections into the cavities. Theinternal walls of the cavities may have one or more array of suchprojections. The array of projections may be considered to be a phononicstructure, in the sense that it is based on a periodic arrangement (inthe manner disclosed in WO 2011023949, WO 2011060369, WO 2012114076 andWO 2012156755) for affecting the distribution and/or transmission ofSAWs in the cavities. In the case of one or more pillars, there may beprovided one or more support struts extending to the pillar to hold itin position. This is particularly the case if the cavity has two openends (i.e. extends through the superstrate) since in this case there isno base of the cavity for the pillar to be supported on.

Such internal structure interact with the liquid and with the SAWs in amanner which can further improve the performance of the cavities inrestricting the droplet size distribution.

The cavities preferably have substantially the same dimensions.

Preferably the depth of the cavities is at least 1 μm. Preferably thedepth of the cavities is at most 1 mm, more preferably at most 500 μm.In some embodiments, the cavities can be blind cavities. However, inother embodiments the cavities can open at a surface opposite to the SAWtransmission surface. This is preferred, for example, where the liquidto be nebulised is fed to the cavity from one or more reservoirs.

Preferably the maximum dimension of the cavities in a directionperpendicular to the depth of the cavities is at least 1 μm. This lowerlimit is set in view of the preferred lower limit for droplet size. Thelower limit may be at least 2 μm, at least 5 μm, at least 10 μm, atleast 20 μm, at least 30 μm, at least 40 μm or at least 50 μm.Preferably, this maximum dimension is at most 500 μm, more preferably atmost 400 μm, at most 300 μm or at most 200 μm. Where the cavities have acircular cross section shape, this dimension is referred to as thediameter of the cavities. Where the cavities have a non-circular crosssectional shape, this maximum dimension is also referred to as thediameter.

The present inventors have considered the effect of this dimension onthe efficacy of the invention. Capillary waves, in the context of thepresent invention, can be considered to be waves which are capable oftravelling along the free surface of the liquid, whose dynamics aredominated by surface tension effects. In common terminology, they can beconsidered to be “ripples” in the manner of ripples on the surface of abody of water. Capillary waves in a body of liquid constrained in acavity can be produced at a fundamental vibrational mode, and/or atharmonic vibrational modes. Without wishing to be bound by theory, it isconsidered to be of importance to restrict the ability of the volume ofliquid contained in the cavity to support capillary waves at thefundamental mode and preferably also at harmonic modes (particularlylower harmonic modes). This is because it is considered that suchcapillary waves would otherwise be responsible for the formation ofrelatively large droplets.

Therefore it is preferred that the diameter of the cavities is suitableto reduce or prevent the formation of such capillary waves in the liquidcontained in the cavities. Put simply, at least for relatively lowoperational frequencies (in the kHz range, for example, i.e. less than 1MHz), the diameter D of the cavities is preferably less than thewavelength of capillary waves which could otherwise be formed in theliquid at the driving frequency f.

The driving frequency f can be considered to be responsible for thegeneration of capillary waves at a fundamental mode of vibration and/orat one or more harmonic modes of vibration. The order of the mode ofcapillary vibration can be denoted m. The frequency of a particular modeof capillary vibration can be denoted f_(m).

The driving frequency f may be identical to f_(m), but in many cases fis only loosely correlated with f_(m). Therefore f_(m) can vary withrespect to f, typically within a range such as:

(f _(m))^(l) ≦f≦(f _(m))^(h)

l is the exponent for the lower limit, and l is 0.5, more preferably0.6, 0.7, 0.8, 0.9 or 1.0. h is the exponent for the upper limit, and his 1.5, more preferably 1.4, 1.3, 1.2, 1.1 or 1.0.

Preferably, at least the fundamental capillary vibration mode issuppressed. Therefore preferably m=0 at least. However, additionally oralternatively low order harmonic capillary vibration modes may besuppressed. Therefore in some embodiments, one or more of m=1, m=2, m=3,m=4, m=5, m=6, m=7, m=8, m=9, m=10 and optionally higher, applies.

The progression of resonant responses from the fundamental mode upwardare provided by the Lamb model, as set out in Blamey et al (2013), whichapplies in particular to the elastic resonance of a spherical capillarysurface but applies within a reasonable approximation in preferredembodiments of the present invention in which the liquid is held incavities:

$f_{m} = \sqrt{\frac{\left( {m + 1} \right)\left( {m + 2} \right)\left( {m + 4} \right)\gamma}{3\; {\pi\rho}\; L^{3}}}$

where L, f_(m) and m are as defined above, γ is the surface tension ofthe liquid in the cavity and ρ is the density of the liquid.

Blamey et al (2013) provides a list of modes, with specific frequencies(f_(m)) and lengths (L_(m)). These are eigenvalues and L_(m) representthe size of the deformation at the interface. The cavities (diameter D)should preferably be smaller than L_(m).

The present inventors consider that the effect of locating the liquid inthe cavities is that, under a particular SAW excitation frequency f, theliquid is pinned by the cavities, suppressing or forbidding capillarywaves which would otherwise form under those conditions, therebysuppressing the generation of large droplets by such capillary waves.

It is considered to be important that liquid emanating from a cavitydoes not come into contact with neighbouring cavities or liquid fromneighbouring cavities. This is because such contact would increase thefree surface area of the liquid and as such increase the degrees offreedom and enable larger wavelength capillary waves to form. As such,depth of the cavity or its shape or the surface chemistry close to thenebulising surface can be important to ensure efficient pinning of thecontact line. Suitable depth of the cavities can be between 500 and 50μm. The deeper the cavity (for a particular cross section shape anddiameter) the more liquid that can be nebulised in one ‘charge’. Throughhole-type cavities have been used having a depth of 380 μm, but such adepth is determined by the thickness of the substrate (or superstrate)in which the cavity is formed, rather than a functional limitation.

As mentioned above, preferably the cavities have substantially the samedimensions. However, it is allowable for the cavities to have adistribution of dimensions. In terms of the diameter of the cavities,preferably the standard deviation of the diameter is 40% or less, morepreferably 30% or less, more preferably 20% or less.

The cavities can be in the form of cylindrical holes. As indicatedabove, in some embodiments the holes can be blind holes. In otherembodiments, the holes can be holes which open also at an opposingsurface to the SAW transmission surface, in order that additional liquidcan be fed into the cavities by capillarity. A suitable volume for thecavities in either can be at least 0.5 nl, more preferably at least 1nl. This volume is preferably at most 50 nl, more preferably at most 20nl, more preferably at most 10 nl, more preferably at most 5 nl. As anexample, a cylindrical hole of diameter 100 μm and depth 300 μm has avolume of about 2 nl.

The array of cavities may not have long range order. In this case, thearrangement of the cavities may be substantially random, in the sense ofnot being based on a periodic arrangement.

It is preferred that the cavities have an average cavity-to-cavitynearest neighbour spacing (measured from the central axis of eachcavity) of at least 10 μm. This is suitable for SAWs in the MHz region(e.g. of frequency of around 100 MHz). More preferably, this spacing isat least 20 μm, at least 40 μm, at least 60 μm, at least 80 μm, or atleast 100 μm. This spacing may be at most 5 mm (corresponding torelatively low frequency SAWs), more preferably at most 4 mm, morepreferably at most 3 mm, more preferably at most 2 mm, more preferablyat most 1 mm, more preferably at most 0.9 mm, at most 0.8 mm, at most0.7 mm, or at most 0.6 mm. For example, a cavity-to-cavity nearestneighbour spacing in the range 200-500 μm has been shown to be suitable.For higher frequencies, e.g. in the GHz range, smaller spacings arecontemplated, e.g. in the range down to at least 1 μm. Spacing betweenthe cavities is considered to be important in order to prevent liquidmerging as it escapes from adjacent cavities.

The frequency of the surface acoustic wave may be in the range of about10 kHz to about 1 GHz, preferably about 1 MHz to about 100 MHz, morepreferably about 5 MHz to about 50 MHz, more preferably about 5 MHz toabout 20 MHz, more preferably about 15 MHz to about 5 MHz, morepreferably between about 13 MHz and about 8 MHz. The frequency of thesurface acoustic wave may be about 12 MHz, about 11 MHz, about 10 MHz,about 9 MHz or about 8 MHz.

The SAW transducer may be formed from any suitable material forgenerating surface acoustic waves. SAWs may be generated, for example,by a piezoelectric process, by a magnetostrictive process, by anelectrostrictive process, by a ferroelectric process, by a pyroelectricprocess, by a heating process (e.g. using pulsed laser heating) or by anelectromagnetic process. It is most preferred that the SAW generationmaterial layer is formed from a piezoelectric layer. In the disclosureset out below, the term “piezoelectric layer” is used but is itunderstood here that similar considerations would apply to SAWgeneration material layers formed, for example, of magnetostrictivematerials. Therefore, unless the context demands otherwise, the optionalfeatures set out in relation to the “piezoelectric layer” are to beunderstood as applying more generally to the SAW generation materiallayer, when formed of any suitable material.

The present inventors further consider that the present invention is notnecessarily limited to the use of SAWs. It is considered thatnebulisation using other acoustic waves, such as bulk acoustic waves, ispossible using the principles of the present invention. Such acousticwaves are susceptible of manipulation in a similar manner to SAWs. Bulkacoustic waves, for example, give rise to corresponding acoustic wavesor displacements at a free surface. Therefore, in the presentdisclosure, it is to be understood that SAWs are only one example of asuitable acoustic wave which can be used to provide suitablemanipulation of a sample. Thus, although in this disclosure the terms“SAW”, “surface acoustic wave”, “SAWs” and “surface acoustic waves” areused, it is to be understood that these may be substituted orsupplemented by the terms “bulk acoustic wave” and “bulk acoustic waves”or the terms “acoustic wave” and “acoustic waves”, unless the contextdemands otherwise.

Preferably, in use, when the SAW transmission surface is facing upwards,the liquid is contained in the cavities such that the free surface ofthe liquid is below the level of the SAW transmission surface. Thus, itis preferred that the free surface of the liquid is not located at orabove the level of the SAW transmission surface. This allows the liquidcontained in the cavities to be isolated from each other, forbidding theformation of capillary waves at the liquid contained in the cavities.

The interior surface of the cavities may be treated in order to promotethe containment of the liquid in the cavities. For aqueous liquids,preferably the interior surface of the cavities is formed to behydrophilic. For non-aqueous liquids, preferably the interior surface ofthe cavities is formed to be hydrophobic.

Additionally or alternatively, the SAW transmission surface may betreated in order to promote the containment of the liquid in thecavities. For example, this treatment may be selectively carried out atthe array of cavities intended to contain the liquid. For aqueousliquids, preferably the SAW transmission surface is formed to behydrophilic. For non-aqueous liquids, preferably the SAW transmissionsurface is formed to be hydrophobic. Preferably, an area of the SAWtransmission surface at which it is not intended for the liquid to belocated is formed to be hydrophobic or hydrophilic, respectively, topromote the location of the liquid at the array of cavities intended tocontain the liquid.

Preferably, operation of the device results in a nebulised plume ofdroplets of average diameter in the range 1-5 μm. Preferably, thedroplet diameter is measured by laser diffraction. Such measurementsprovide a droplet size distribution curve in the form of a number-baseddistribution (i.e. number of droplets is shown on the ordinate anddiameter of droplets is shown on the abscissa).

The respirable fraction of the droplets can be defined as the integralof the droplet size distribution in the diameter range 1-5 μm (N₁₋₅)divided by the integral of the droplet size distribution over the totaldiameter range measured (N_(total)). Thus, respirable fraction can bedefined as (N₁₋₅)/(N_(total)).

Preferably, operation of the device results in a nebulised plume ofdroplets with a respirable fraction of at least 80%, preferably at least85%, more preferably at least 90%, more preferably about 95% or higher.

In the prior art, it is known to filter out larger droplets from anebulised plume in order to restrict the droplet size distribution whichreaches the subject. However, this reduces the efficiency of the device,by reducing the proportion of the dose which reaches the subject, andclogging is also a problem, wherein captured large droplets preventsubsequent smaller droplets from being passed through. In the presentinvention, it is preferred that the respirable fraction is determined onthe basis of the nebulised plume formed from the cavities, and notsubjected to filtration prior to determination of the droplet sizedistribution.

In preferred embodiments, the present invention may provide supply ofliquid for nebulisation. Since the cavities are relatively small, it maybe preferred to ensure a supply of additional liquid for nebulisation.This supply may be continuous, in the sense that liquid is supplied tothe cavities for nebulisation while nebulisation is being carried out.Alternatively, this supply may be intermittent, in the sense that liquidis supplied to the cavities after some liquid has been nebulised fromthe cavities and before nebulisation of the additional liquid is begun.This alternative approach can be considered to be a repeatingnebulisation approach.

Preferably, the device is capable of nebulising the liquid at a rate ofat least 5 ml/min.

The liquid may have relatively high viscosity, because the mechanism ofthe nebulisation provided in the present invention can toleraterelatively high viscosity. The viscosity of the liquid (measured at roomtemperature) may be at least 0.5 mPa·s, but in some embodiments may beat least 1 mPa·s, at least 5 mPa·s, or at least 10 mPa·s. For reference,at room temperature ethanol has viscosity of 1.07 mPa·s, bovine serumalbumin 5% in phosphate buffer has viscosity of 1.5 mPa·s, glycerol hasviscosity of 1200 mPa·s and water has viscosity of 0.894 mPa·s.

The surface tension of the liquid (measured at room temperature) may beat least 10 mN/m. In some embodiments, the surface tension may be atleast 50 mN/m. For reference, at room temperature ethanol has a surfacetension of 22.1 mN/m, bovine serum albumin 5% in phosphate buffer has asurface tension of 55.0 mN/m, glycerol has a surface tension of 63.0mN/m and water has a surface tension of 71.9 mN/m.

The supply of liquid may be provided, for example, by a syringe pump.Other metered liquid supply systems may be used.

In order to supply additional liquid to the cavities, it is possible forthe cavities to be open at their end distal from the SAW transmissionsurface. In that case, the distal ends of the cavities may be in fluidcommunication with a reservoir of the liquid, to be drawn up bycapillarity into the cavities to replace liquid lost by nebulisation. Inthis case, it is possible for the liquid to be used as the couplingagent for the superstrate.

In order to provide adequate rate of nebulisation, the device mayinclude a plurality of arrays of cavities, in order that there is asuitable number of cavities operating to contribute to the rate ofnebulisation (in terms of the volume of liquid nebulised in total by thedevice per unit time). These may each be associated with a correspondingrespective SAW transducer. However, it is possible for the plurality ofarrays of cavities to be operated using a single SAW transducer. Inorder to provide a suitable distribution of SAWs to the respectivearrays of cavities, the device may include phononic arrays, as set outin WO 2011023949, WO 2011060369, WO 2012114076 and/or WO 2012156755, inorder to concentrate the SAW distribution as required at the respectivearrays of cavities.

Further optional features of the invention are set out below.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the invention will now be described by way of examplewith reference to the accompanying drawings in which:

FIG. 1A shows a schematic plan view of a device according to anembodiment of the invention, in the form of an etched array of cavitiesin a superstrate on an interdigitated electrode transducer (IDT)surface.

FIG. 1B shows a cross sectional view of the device of FIG. 1A.

FIG. 2 shows the results of droplet size distribution (number-based)analysis of droplets generated from nebulisation (a) an embodiment ofthe present invention, with the liquid contained in cavities in asilicon superstrate coupled on a SAW device with excitation frequency of8.6 MHz and input power of 1.5 W (b) Medix nebuliser (c) Medisananebuliser and (d) directly on the SAW device of (a) with excitationfrequency of 8.6 MHz and input power of 1.5 W.

FIG. 3 shows the respirable fraction of nebulised droplet generated fromthe commercialised nebulisers (Medix (3) and Medisana (4)), directly onSAW devices (2) on silicon superstrate coupled on the SAW device (1)with excitation frequency of 8.6 MHz and input power of 1.5 W

FIG. 4A shows a micrographic image captured from a video of nebulisationat 11.762 MHz and −4 dBm of DI water at 2 μl/min on a plain surface.Large individual drops are seen due to free capillary microjets at thesurface of the drop.

FIG. 4B shows a micrographic image captured from a video of nebulisationat 11.762 MHz and −4 dBm of DI water at 2 μl/min located in cavitiesarranged as a phononic lattice (900 μm diameter). No large individualdrops are seen. As a guide to the scale of the images of FIGS. 4A and4B, the syringe shown in the image is a 1 ml syringe, with a syringebody diameter of 5 mm.

FIG. 5 shows a schematic cross sectional view of a single cavity.

FIG. 6 shows a schematic cross sectional view of a single cavity whichis a modification of the cavity shown in FIG. 5.

FIG. 7 shows a schematic cross sectional view of a single cavity whichis another modification of the cavity shown in FIG. 5.

FIG. 8 shows a plan view of the cavity of FIG. 7.

FIG. 9 shows a schematic cross sectional view of a single cavity whichis a modification of the cavity shown in FIG. 8.

FIG. 10 shows a plan view of the cavity of FIG. 9.

FIG. 11 shows a graph of droplet size with cavity (pore) diameter, basedon an assessment of largest droplet size viewed in video footage.

FIGS. 12-14 show images from high frame rate video footage taken using amicroscope when water is nebulised from cavities of diameter 80 μm (FIG.12), 600 μm (FIG. 13) and 1500 μm (FIG. 14).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS, AND FURTHER OPTIONALFEATURES OF THE INVENTION

Before discussing the features of the preferred embodiments of thepresent invention in detail, it is useful to consider the features andperformance of known ultrasonic nebulisers.

Ultrasonic nebulisers use the basic principle of applying a highfrequency mechanical vibration to a surface. This leads to theexcitation of deformations on the free liquid surface that result inmicrojets [Topp (1973)]. These nebulisers enable the atomisation of awider range of liquids than other types of nebulisers (such as jet orcompressed air). However the aerosol produced suffers from wide range ofdroplet size. Recently this principle has been extended to the use ofSAWs [Reboud, Wilson et al (2012); Qi et al (2009)], which offer theadvantages of lower powers and more versatility in integration ofpreparation functions. However these suffer from similar limitations inthe control of the drop size, which generally leads to large meandiameters (above 10 μm) and multiple modes.

To provide a tight droplet size distribution, meshes have beenintroduced as passive filters (MicroAir™—OMRON, and microflow—Pfeiffer)situated after the nebulisation process, to select the drops of thecorrect size. These systems require careful maintenance (to preventclogging) and show limited efficiency.

Vibrating meshes combine both approaches at the site of nebulisation[Maehara et al (1986)]. A mesh of apertures is vibrated at ultrasonicfrequencies to generate the aerosol from a pinching off of the dropsthrough the aperture, in a similar mechanism as the microjets mentionedpreviously for SAW nebulisation. A similar system is commercialised fordroplet dispensing (Scienion AG).

In the preferred embodiments of the present invention, the array ofcavities is used to prevent the pinching off enabled by the vibratingmeshes and thus provide the opportunity of a reduced size withoutrequiring fine apertures (on the order of the size of the dropdispensed). This provides a cheaper manufacturing strategy. It is alsonot reliant on the surface properties of the mesh and thus can tolerateconditions that would lead to significant clogging, enabling thedispensing on difficult suspensions, such as those with high viscosity.

Qi et al [2009] have shown nebulisation off a paper superstrate, usingSAW. Although the paper superstrate could be viewed as a mesh, theirwork clearly show no capillary wave limiting effect on the selection ofdroplet sizes (see FIG. 6 of Qi et al [2009], clearly showing large(i.e. greater than 10 μm) droplets). This is due to the widedistribution of pore sizes compared to the embodiments presented here.Indeed, in their work, the paper superstrate is used as a matrix to feedthe liquid, while the nebulisation happens in a bulk mode (as a drop—seeFIG. 2c of Qi et al [2009]).

A preferred embodiment of the present invention is illustratedschematically in FIGS. 1A and 1B. This is based on the inventors'previous SAW-based systems [see WO 2011023949, WO 2011060369, WO2012114076, WO 2012156755, Reboud, Wilson et al (2012) and Reboud,Bourquin et al (2012)].

The device includes a LiNbO₃ actuator 10 (single crystal,self-supporting) with an interdigitated electrode 12 and a Sisuperstrate 14, with etched blind holes 16. The holes (i.e. cavities)are arranged in a square periodic lattice array. A liquid (the sample)18 is positioned inside the cavities. Thus, the height of the liquid inthe cavities is less than the depth of the cavities. This is ensuredusing highly hydrophilic wetting and a small sample volume.

Upon actuation, the SAW propagates on the SAW transmission surface (theupper surface of the actuator 10) and is coupled onto the superstrate14, via a coupling medium (not shown) such as gel or water or glue or amore permanent fixture (the array of cavities can be deposited on oretched into the piezoelectric layer). The material of the superstrate 14is preferably acoustically non-dampening (e.g. Si or glass).

The superstrate 14 holding the array of cavities can be fully in contactwith the piezoelectric actuator 10 (as shown in FIGS. 1A and 1B) orcoupled only using a small overlap.

The SAW then interacts with the liquid contained in the cavities 16.This interaction creates a nebulised plume. Here the cavities are usedto prevent the creation of microjets of sizes greater than about 10 μmthat result in multimodal droplet distribution. The specific mechanismfor this is still under investigation by the inventors. Without wishingto be limited by theory, the present inventors believe that themechanism is linked to the damping, suppression or forbidding ofcapillary waves propagating at the free surface of the liquid in thecavities. This capillary mechanism has been reported as the primarymechanism for nebulisation using SAW [Qi et al (2008)], and leads tosizes outside the range of interest for drug delivery.

In more detail, the SAW actuator 10 and the superstrate 14 aremanufactured as follows. Positive photoresist, S1818 (Shipley) was usedto lithographically define the electrode pattern on the 127.8° Y-cutLiNbO₃ substrate. After the resist exposure and development, 10 nm oftitanium and 100 nm of gold were deposited and lift-off was performed inacetone.

The superstrate was fabricated using <100> silicon wafer and standardoptical photolithography. The array of cavities was constructed usingdry etch (STS ICP), down to half the wafer thickness (about 250 μm).Control experiments were carried out on unpatterned superstrates as wellas on the LiNbO₃ actuator.

In order to control the volumes and shape of drops deposited on thesurface as well as to create controlled spatial areas for nebulisation,the superstrate was patterned with a hydrophobic silane using standardoptical lithography. The process involved developing the exposed S1818photoresist (Shipley) and surface treatment in O₂ plasma beforesilanisation in a solution of trichloro (1H, 1H, 2H, 2H perfluorooctyl)silane (Aldrich) in heptane (Aldrich). The superstrate was then rinsedin acetone to create hydrophilic (untreated) spots of varying sizes inthe range of 1-15 mm on a hydrophobic surface.

The frequency response of the SAW actuator was observed using a networkanalyser (E5071C ENA Series, Agilent Technologies). To performnebulisation of the liquids on the substrate, a high frequencyelectrical signal was supplied to the electrodes using a MXG AnalogSignal Generator (N5181A, Agilent Technologies) and amplifier (ZHL-5W-1,MiniCircuits).

The silicon superstrate and the piezoelectric substrate were assembledwith KY-jelly (Johnson & Johnson) between them to provide efficientcoupling.

Measurements of droplet size were performed at 8.64 MHz at the inputpower of 1.5 W. A sessile drop of 3 μL of deionised (DI) water was usedfor each nebulisation using the embodiment device of the invention. Ascomparisons, the nebulised droplet size by two commercialisednebulisers, Medix and Medisana were also measured. The Microneb Medixuses a titanium vibrator which oscillates at approximately 180 kHz withinput power of 1.5 W to generate the droplet which is then passingthrough metal alloy mesh. The Medisana is an ultrasonic nebuliser thatoperates at 100 kHz with input power of 3 W.

The distributions of nebulised droplet with different sizes weremeasured using a laser diffraction technique (Spraytec, MalvernInstruments Ltd, UK) and represented in the form of a frequencydistribution curve.

The diameters of the nebulised droplet has been reported by Kurosawa etal (1995) by using a number distribution. They obtained the linear meandiameter, D10 and surface mean diameter, D32 of 19.2 μm and 34.3 μm,respectively for tap water nebulised directly on a SAW device withexcitation frequency of 9.5 MHz and input power of 2.5 W for 0.1 ml/minnebulisation rate. The droplet size distribution had two modes withpeaks at 10 μm and 40 μm which were reported to be due to the capillarywavelength and the intermittent burst drive, respectively. Smallerdroplets (D₁₀=6.8 μm and D₃₂=15.0 μm) were obtained using SAW devicewith higher excitation frequency of 48 MHz and lower input power of 2.3W for 170 μl/min nebulisation rate [Kurosawa et al (1997)]. Alvarez etal (2007) successfully nebulised insulin with mean diameter of 4.5 μmusing 19.3 MHz SAW device at 0.3 W input power. By using the same imageprocessing technique as previous authors, Ju et al (2008) estimated themean diameters of nebulised bovine serum albumin (BSA) to be 5.7, 4.4and 2.7 μm using SAW devices with excitation frequencies of 50, 75 and95 MHz, respectively. Smaller droplets with mean diameters of 0.36, 0.38and 0.4 μm were obtained using 10 MHz SAW device with input power of0.97, 1.00 and 1.03 W, respectively [Ju et al (2010)].

FIG. 2 shows the distribution obtained for the different surfaces used.They are presented as frequency distributions. The results show thatboth commercial nebulisers, utilising an ultrasonic technology, providedrop sizes above the optimum size for lung penetration (modes above 5μm). These distribution are also broad, leading to significant wastageof the targeted therapy.

As shown in FIG. 2, SAW nebulisation from a plain surface is able toprovide a smaller droplet size than the commercial nebulisers, whichwould fit the therapeutically-relevant range (between 1 and 5 μm).However this actuation leads to secondary peaks (large sizes above 10μm), and a broad distribution. These features lead to inefficientnebulisation and wastage of the liquid.

Using the array of cavities to contain the liquid for nebulisationenables the prevention of large secondary peaks, and sharpens thedistribution of the peak (1-5 μm) of interest.

The results can be presented using the concept of respirable fraction,which reports the proportion of the total size distribution that isenabled by the different systems (the ratio of integral below the curvesbetween 1 and 5 μm, over the total integral), as shown in FIG. 3, whilethe data analysed is presented in Table 1.

TABLE 1 Derived parameters of the nebulised droplets generated by thesurface acoustic waves devices and commercialised nebulisers measuredusing the Malvern Spraytec SAW + Si SAW superstrate (transducer Medixwith cavities only) Microneb Medisana Linear mean 1.81 ± 0.13  1.32 ±0.18 3.00 ± 0.27  5.73 ± 0.94 diameter, D_(v)10 (μm) Linear mean 2.10 ±0.16  5.21 ± 6.87 5.84 ± 0.49 13.19 ± 1.89 diameter, D_(v)50 (μm) Linearmean 2.50 ± 0.30 52.28 ± 4.06 11.09 ± 1.06  27.13 ± 6.64 diameter,D_(v)90 (μm) Surface mean 2.16 ± 0.17  3.38 ± 0.82 5.13 ± 0.64 10.04 ±1.71 diameter, D₃₂ (μm) Volume mean 3.45 ± 2.24 17.88 ± 3.47 6.54 ± 0.5715.06 ± 2.93 diameter, D₄₃ (μm) % Respirable 96.16 ± 4.93  36.44 ± 6.2538.38 ± 6.14   6.92 ± 2.89 Fraction (1 μm < D < 5 μm)

In order to increase the quantity nebulised and establish thesteady-state properties of the system, a syringe pump (NE-1000Multi-Phaser™, New Era Pump Systems Inc.) was employed to regulate theamount of liquid supplied to the superstrate continuously. The pump wasset to a constant flow rate of 1.0 μl/min to maintain continuousproduction or rapid generation of nebulised droplets.

FIGS. 4A and 4B show example frames extracted from movies on a plainsuperstrate (FIG. 4A) and on a superstrate having an array of cavities(FIG. 4B), illustrating the proposed hypothesis that the array ofcavities prevents the generation of larger droplets.

The cavities can be formed to extend through the superstrate. Thisallows the cavities to be replenished with additional liquid by fillingfrom below under capillarity. This allows the delivery of the liquid tobe more robust. In this embodiment the liquid can also be used as thecoupling agent.

Using a single spot and powers below 1 W, the illustrated embodimentenables flow rates around 20 ul/min. The flow rate can be increasedsignificantly by increasing actuation power (up to 5-10 W) for a shortperiod of time (<5 s).

In order to further increase the flow rate, there may be provided aplurality of locations (each having an array of cavities) at whichnebulisation is carried out substantially simultaneously. In this way,the flow rate can be increased to 5 ml/min, or higher.

It is preferable to establish the nebulisation in specific areas,defined by wetting barriers. However, in the case of isotropicexcitation on large arrays of cavities, the liquid may then be assembledin patches by irregularities and build up in volumes that are locallybulging above the surface of the SAW transmission surface of thesuperstrate. This behaviour would prevent the activity of the cavitiesand would result in multimodal droplet sizes, due to microdropletejection. Thus, it is instead preferred to provide wetting channels atthe interface between the superstrate and the piezoelectric actuator.Such channels can also serve as acoustic waveguides to channel the SAWsto the nebulisation areas.

In preferred embodiments, a suitable cavity diameter is 50-200 μm. Theeffect of the diameter on the ability of liquid in the cavities tosupport capillary waves can be considered based on the driving frequencyf. As explained above, the diameter D of the cavities is preferablylower than a size that would allow the generation of unwanted largedroplets, thought to be the result of unwanted capillary waves.

The theoretical framework for the mechanism of large droplet suppressionis not fully understood at the time of writing. The application of theprogression of resonant responses from the fundamental mode upward,provided by the Lamb model, as set out in Blarney et al (2013), can beconsidered in which, for the sake of simplicity, the driving frequency fcan be considered to be identical to fm for the fundamental mode. Whilstthis is effective for low frequencies (in the kHz range or below) it isnot effective for MHz range driving frequencies, for reasons which arenot fully understood at the time of writing.

It is therefore more suitable here to take an empirical approach to thedesign of the cavities. FIG. 2(d) shows that nebulisation on a flatsurface gives rise to a bimodal distribution. However, for the intendeduse of the nebulised droplets, the second peak (larger drops) is notwanted. In a preferred embodiment of the invention, cavities are formed(cylindrical holes in a superstrate to be coupled to the SAW transducer)having dimensions that prevent the capillary wave instability, in orderto suppress or avoid the formation of the larger droplets. In FIG. 2(d),the second peak is centred on about 40 μm. Therefore the diameter of thecavities can be controlled to be less than 40 μm. This indeed will showa performance in which the larger droplets are suppressed. The inventorsalso report that the drop formation requires deformations of the surfacethat are of a scale larger than the drop size. FIG. 4 for example showsthat cavities of diameter 80 μm still prevent the bigger drops. Furtherresults (not shown) have demonstrated that cavities up to 200 um indiameter can also prevent these secondary drops.

In the schematic view shown in FIGS. 1A and 1B, the cavities 16 have ashape which is substantially hemispherical. This is intended to beillustrative. Hemispherical cavities can be used. However, moregenerally, cavities of other shapes can be used, e.g. cylindricalcavities, rectangular or square cylindrical cavities, circularcylindrical cavities, etc. Such cavities can have closed bottom ends.The bottoms of such cavities can be flat or rounded. In the case ofetched cavities, some rounding of the bottoms is typical.

In other embodiments, the cavities may have more complex internalstructures. Examples are shown in FIGS. 5-10.

FIG. 5 shows a schematic cross sectional view of a single cavity 40. Thecavity has a closed bottom 42, internal walls 44, 46 and an upstandingpillar 48. Pillar 48 is supported on the closed bottom 42. In the cavityof FIG. 5, it is intended that the plan view shape of the cavity is asquare, with the pillar formed at the centre. In alternativeembodiments, the plan view shape of the cavity may be rectangular, otherpolygonal shape, round or circular. In those cases, it is possible forthe pillar to be located at the geometrical centre of the shape, orlocated off-centre.

FIG. 6 shows a schematic cross sectional view of a single cavity 60which is a modification of the cavity shown in FIG. 5. Here, theinternal walls 64, 66 and the pillar 68 have an array of projections 67.The projections are arranged based on a periodic arrangement with theintention of interacting phononically with SAWs and affecting thetransmission, distribution or other properties of the SAWs in thecavity. In this way, a phononic structure 69 is formed.

FIG. 7 shows a schematic cross sectional view of a single cavity 80which is another modification of the cavity shown in FIG. 5. The cavityhas an open bottom 82, internal walls 84, 86 and an upstanding pillar88. Since there is no closed bottom to support pillar 88, it issupported by an arrangement of struts 90 extending from the internalwalls 84, 86. As for the cavity of FIG. 5, it is intended that the planview shape of the cavity is a square, with the pillar formed at thecentre. In alternative embodiments, the plan view shape of the cavitymay be rectangular, other polygonal shape, round or circular. In thosecases, it is possible for the pillar to be located at the geometricalcentre of the shape, or located off-centre.

FIG. 8 shows a plan view of the cavity of FIG. 7.

FIG. 9 shows a schematic cross sectional view of a single cavity 100which is a modification of the cavity shown in FIG. 8. Here, theinternal walls 104, 106 and the pillar 108 have an array of projections107. The projections are arranged based on a periodic arrangement withthe intention of interacting phononically with SAWs and affecting thetransmission, distribution or other properties of the SAWs in thecavity. In this way, a phononic structure 109 is formed. Pillar 108 issupported by struts 110.

FIG. 10 shows a plan view of the cavity of FIG. 9.

The use of complex cavity structures allows the interaction of the SAWswith the liquid to be controlled further. This is achieved byconsideration of interaction of the fluid with the additional structuresand by consideration of the interaction of the SAWs with the additionalstructures.

Additional investigation has been carried out to assess the effect ofcavity size (also referred to herein as pore size) on aerosol dropletsize. Cavities of different diameter were etched into siliconsuperstrates. The cavities were etched cylindrical pits with a closedbottom end, approximately 300 μm deep. Using blind cavities in this waydid not allow a continuous feeding of the cavities with liquid. As aresult, for each experiment, only a small volume could be nebulised at atime. For this reason, rather than carrying out an analysis of theparticle size distribution based on light diffraction, as reportedabove, here the results are reported based on a visual observation of asmall number of drops in the nebulised plumes (based on recordedmicrovideograph footage of the nebulised plumes).

Initially, a drop of water was placed on top of each superstrate and SAWwas applied until the top layer of water disappears (either evaporate ornebulised), leaving water only in the cavities without there beingliquid communication between the cavities (no water present on thesurface of the superstrate between the cavities). Nebulisation from thecavities was then monitored using a fast camera (>250 kfps) fixed to amicroscope, enabling the recording of images.

The largest droplets nebulised from the pores were visually assessed fortheir diameters.

The results are shown in FIG. 11. FIGS. 12, 13 and 14 show images fromthe recorded footage, with FIG. 12 showing a superstrate with cavitiesof diameter 80 μm, FIG. 13 showing cavities of diameter 600 μm and FIG.14 showing cavities of diameter 1500 μm. For each, the SAW was excitedat 13.93 MHz and −5 dBM. The series of images was analysed and largestdroplets were measured. Note that to estimate droplet size from the 80μm cavities, the thickness of the plume were divided by the number ofdroplets (3 to 4 droplets) and for holes with 600 and 1500 μm diameter,single droplets were measured. For the 80 μm cavities, this was becausethe plume was so condensed that no single droplet could be measured.

FIG. 11 shows the variation in droplet size with cavity diameter. Thisshows an increase in droplet size as the cavity diameter is increased.However, the change in droplet size is not as significant as expected,but this is likely to be due to the measurement approach. Measurement ofthe droplet diameter distribution using light scattering in a continuousplume would demonstrate a shift in droplet size distributions, in whichfor small cavities (80 μm diameter), only small drops are present (<10μm), whereas for larger cavities (1500 μm diameter), small drops arestill seen, but other modes also exist to provide droplets also of largediameter (about 20-50 μm mean size). The results reported here indicatean effect attributable to the cavity diameter and correlate with thetheory outlined, which is that the pinned surface layer within pores isruled by the meniscus curvature (i.e. contact angle with pore wall).This results in a surface rigidity, suppressing capillary waves.

While the invention has been described in conjunction with the exemplaryembodiments described above, many equivalent modifications andvariations will be apparent to those skilled in the art when given thisdisclosure. Accordingly, the exemplary embodiments of the invention setforth above are considered to be illustrative and not limiting. Variouschanges to the described embodiments may be made without departing fromthe spirit and scope of the invention.

All references referred to above are hereby incorporated by reference.

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1. A device for the preparation of nebulised droplets, the devicehaving: a surface acoustic wave (SAW) transmission surface; a SAWtransducer adapted to generate and propagate SAWs along the SAWtransmission surface; and an array of cavities opening at the SAWtransmission surface for containing a liquid, wherein, in operation,SAWs propagating along the SAW transmission surface interact with theliquid in the cavities to produce nebulised droplets of the liquid. 2.The device according to claim 1 wherein the SAW transmission surface isa surface of a superstrate coupled to the SAW transducer.
 3. The deviceaccording to claim 1 wherein the cavities have substantially the sameshape.
 4. The device according to claim 1 wherein the cavities havesubstantially different shapes.
 5. The device according to claim 1wherein the cavities form an array of cavities of substantially randomshapes.
 6. The device according to claim 1 wherein the cavities areclosed at an end distal from the SAW transmission surface.
 7. The deviceaccording to claim 1 wherein the cavities are open at an end distal fromthe SAW transmission surface.
 8. The device according to claim 1 whereinthe cavities have substantially the same dimensions.
 9. The deviceaccording to claim 1 wherein the array of cavities is an ordered array.10. The device according to claim 1 wherein the array of cavities doesnot have long range order.
 11. The device according to claim 1 whereineach cavity has an interior surface, said interior surface of thecavities being chemically, physically or electrically modified in orderto promote the containment of the liquid in the cavities.
 12. The deviceaccording to claim 1 wherein the SAW transmission surface is chemically,physically or electrically modified in order to promote the containmentof the liquid in the cavities.
 13. The device according to claim 1wherein the device includes a plurality of arrays of cavities, operableto contribute to the rate of nebulisation of liquid from the device. 14.The device according to claim 1 wherein the maximum dimension of thecavities in a direction perpendicular to the depth of the cavities isless than 500 μm.
 15. A method for the preparation of nebuliseddroplets, including providing a device having a surface acoustic wave(SAW) transmission surface, a SAW transducer adapted to generate andpropagate SAWs along the SAW transmission surface, and an array ofcavities opening at the SAW transmission surface, the method includingthe steps: containing a liquid in the cavities; and causing SAWs topropagate along the SAW transmission surface to interact with the liquidin the cavities to produce nebulised droplets of the liquid.
 16. Themethod according to claim 15 wherein when the SAW transmission surfaceis facing upwards, the liquid is contained in the cavities such that thefree surface of the liquid is below the level of the SAW transmissionsurface.
 17. The method according to claim 15 wherein operation of thedevice results in a nebulised plume of droplets of average diameter inthe range 1-5 μm.
 18. The method according to claim 15 wherein operationof the device results in a nebulised plume of droplets with a respirablefraction of at least 80%.
 19. The method according to claim 15 furtherincluding the step of supplying liquid for nebulisation.
 20. A methodfor the preparation of nebulised droplets and their delivery to asubject for therapeutic treatment, including providing a device having asurface acoustic wave (SAW) transmission surface, a SAW transduceradapted to generate and propagate SAWs along the SAW transmissionsurface, and an array of cavities opening at the SAW transmissionsurface, the method including the steps: containing a liquid in thecavities; causing SAWs to propagate along the SAW transmission surfaceto interact with the liquid in the cavities to produce nebuliseddroplets of the liquid; and delivery of the nebulised droplets to thesubject for therapeutic treatment by inhalation.
 21. (canceled)